1. Field of the Invention
The invention relates to acid salts of 1-(cyanoalkyl)-4-guanylpiperazines, methods for their preparation, and methods for their use in preparing 1-(cyanoalkyl)-4-(2-pyrimidyl)piperazines (which are in turn useful materials for producing compounds having pharmacological utility as tranquilizing and anti-emetic agents).
2. Description Relative to the Prior Art
It is known that 8-[.omega.-[4-(2-pyrimidyl)-1-piperazinyl]alkyl]-8-azaspiro[4.5]decane-7,9 -diones represented by the structural formula ##STR1## wherein A represents an alkylene group having from 2 to 6 carbon atoms, have pharmacological utility as tranquilizing and anti-emetic agents.
Methods are also known for preparing the compounds of Formula I by using, as starting materials, 1-(cyanoalkyl)-4-(2-pyrimidyl)piperazines represented by the structural formula ##STR2## wherein R represents an alkylene group having from 1 to 5 carbon atoms. Such methods are described, for example, in U.S. Pat. Nos. 3,976,776; 3,907,801; 3,717,634; and 3,398,151, and the disclosures of these patents are hereby incorporated herein by reference.
The aforesaid patents, taken with Howard et al, J. Org. Chem., Vol. 18, pp. 1484-1488 (1953) (which is referred to therein) also describe a method for preparing the compounds of Formula II. For example, for preparing 1-(3-cyanopropyl)-4-(2-pyrimidyl)piperazine, that method includes reacting piperazine with 2-chloropyrimidine to obtain 1-(2-pyrimidyl)piperazine, which is then reacted with 3-chlorobutyronitrile to obtain the desired compound.
However, such a method has a number of drawbacks. Namely, the yields are relatively poor, and the starting material, 2-chloropyrimidine, is relatively expensive. The known method, as described in the references noted above, for producing the Formula II compounds entails a considerable waste of the expensive 2-chloropyrimidine. Part of the reason for the waste is that in reacting piperazine with 2-chloropyrimidine to obtain 1-(2-pyrimidyl)piperazine, a very significant amount of by-product comprising 1,4-bis(2-pyrimidyl)piperazine also results and must be separated out, thus wasting large amounts of 2-chloropyrimidine.
The present invention provides alternative syntheses of the Formula II compounds which do not involve 2-chloropyrimidine. The inventive syntheses involve guanidation of a novel 1-(cyanoalkyl)piperazine to form a novel 1-(cyanoalkyl)-4-guanylpiperazine acid salt, followed by a ring formation reaction to convert the guanyl group to a pyrimidyl group.
In regard to guanidation, Japanese Patent Application Publication (Kokai) No. 51-39680, published Apr. 2, 1976, describes a method of creating a guanyl substituent at one nitrogen atom of piperazine by reacting piperazine with cyanamide in an inert solvent, but it does not describe such a method for guanidating a piperazine which already has a substituent group attached to one of its nitrogen atoms.
Also, in regard to guanidation, U.S. Pat. No. 2,425,341 describes guanidation of some primary and secondary amines having dissociation constants of at least 1.times.10.sup.-6 by slowly adding an aqueous solution of cyanamide with heating to a mixture of the amine and an acid salt of t2he amine at a pH of at least 8, but it does not describe a method for preparing a 1-(cyanoalkyl)-4-guanylpiperazine acid salt from a 1-(cyanoalkyl)piperazine.
In regard to pyrimidyl ring formation, U.S. Pat. No. 4,297,495 describes a method of preparing 2-isopropylamino pyrimidine by reacting bis(isopropylguanidine)sulfate with 1,1,3,3-tetraethoxypropane in acidic aqueous solution, but it does not describe such a method for preparation of a 1-(cyanoalkyl)-4-(2-pyrimidyl)piperazine from a 1-(cyanoalkyl)-4-guanylpiperazine acid salt.
It should be noted that we also have invented other alternative syntheses of Formula II compounds and have invented other novel compounds which are useful in these syntheses. These other inventions are described in our co-pending U.S. patent applications, Ser. No. 407,216, filed Aug. 11, 1982, entitled "Cyanoalkylpiperazines and Methods for Their Preparation and Use" (now U.S. Pat. No. 4,515,947 issued May 7, 1985) and Ser. No. 407,223, filed Aug. 11, 1982, entitled "2-Pyrimidyl Alkanesulfonates and Methods for Their Preparation and Use," the disclosures of which are hereby incorporated herein by reference.